懷孕相關乳癌組織之腫瘤微環境探討

Abstract

背景： 懷孕相關乳癌是指在懷孕期間或是生產後幾年內發現的乳癌。懷孕相關乳癌然相對罕見，並且與較差的預後相關。導致這種不良預後的潛在機制仍未得到充分理解。本研究旨在探討懷孕相關乳癌與腫瘤微環境的關係及影響。 方法： 本研究回顧性納入105名國立台灣大學醫院的乳癌患者。懷孕期間或是生產後五年內確診乳癌的患者定義為懷孕相關乳癌，以相同年齡範圍且未曾生育的乳癌患者作為對照組。腫瘤免疫微環境的評估採用蛋白質多重螢光染色Multiplex immunohistochemistry和基因表現量NanoString BC360 panel兩種分析方法。使用PAM50對乳癌進行分子型態分類。兩組的比較包含基因表現量及路徑分析、免疫細胞總量和分類的比較；同時使用Gene Expression Omnibus (GEO)資料庫進行外部驗證。存活分析的部分採用Kaplan-Meier曲線、Cox迴歸和中介分析，評估免疫細胞對懷孕相關乳癌預後的潛在影響。 結果： 與對照組相比，懷孕相關乳癌於免疫細胞量方面在兩種分析方法中均顯示升高的情形。基因表現差異分析顯示免疫刺激基因活化與免疫調節基因降低。懷孕相關乳癌有著較高的專一性免疫細胞浸潤。細胞毒性CD8+T細胞的浸潤與整體存活率相關。中介分析顯示細胞毒性細胞的中介角色。使用GEO資料庫進行的外部驗證也證實了生產後乳癌病例中免疫細胞的增加。 結論： 本研究顯示懷孕相關乳癌具有不同的免疫微環境。細胞毒性細胞的增加有助於懷孕相關乳癌的預後。待未來大型研究確認免疫細胞與懷孕相關乳癌預後的關係。

Background Pregnancy-associated breast cancer (PABC) refers to breast cancer detected during gestation or within years following childbirth. While relatively uncommon, it is linked to a poor prognosis, and the underlying mechanisms contributing to this adverse illness remain inadequately comprehended. This study examined tumor microenvironment features linked to pregnancy or lactation to elucidate these mechanisms.

Method A total of 105 breast cancer patients from National Taiwan University Hospital were retrospectively included in the current investigation. Patients with breast diagnosis within 5 years postpartum were defined as PABC. Nulliparous breast cancer (NPBC) patients with the same age range were selected as control group. The immune microenvironment was assessed by multiplex immunohistochemistry and NanoString BC360 transcript analysis. PAM50 classification approach was employed for breast cancer classification. Gene expressional difference analysis, immune cell comparison, and functional pathway analysis were done, with external validation conducted using the GEO database. Survival analysis was conducted with Kaplan-Meier curve, Cox proportional hazard model, and mediation analysis to assess the potential influence of immunological features on prognosis of PABC.

Result PABC tumors exhibited elevated immune scores compared to NPBC in both IHC and transcriptome analyses. Differential expression analysis revealed upregulation of immune-active genes and downregulation of immune-regulatory genes. Increased infiltration of adaptive immune cells was noted in PABC. The elevation of infiltrating CD8+ T cells correlated with improved overall survival. Mediation analysis demonstrated that immune characteristics significantly influenced survival outcomes. External validation utilizing GEO databases corroborated the observation of elevated immune cell signatures in postpartum breast cancer cases.

Conclusion This study revealed that PABC exhibit distinct tumor immune microenvironments. The increased cytotoxic cell mediates the favorable prognosis in the PABC group. Additional large-scale study is required to confirm the prognostic significance of immune cells in PABC.